3-(4-phenyl-1 2, 6 di keto piperazinyl)-2-hydroxy-propoxy)-aniline

ABSTRACT

Substituted (3-(4-phenyl-1-piperazinyl)-propoxy or propylthio)anilines prepared, inter alia, by the reaction of the correspondingly substituted propoxy or propyl-thio anilines and N-phenyl-piperazines, are described. The end products, i.e., the substituted (3-(4-phenyl-1-piperazinyl)-propoxy or propyl-thio) anilines are useful as hypotensive agents. These may be prepared via the corresponding 2,6 piperazine diones.

United States Patent [1 1 Edenheter et a1. 7

3-(4-PHENYL-l 2, 6 DI KETO PIPERAZINYL)-2-HYDROXY-PROPOXY)- ANILINEInventors: Albrecht Edenhofer, Riehen; Hans Splegelberg, Basel, both ofSwitzerland Assignee: Hoffmann-La Roche Inc., Nutley,

Filed: July 7, 1972 Appl. No.: 269,680

Related US. Application Data Division of Ser. No. 882,297, Dec. 4, 1969,Pat. No. 3,701,777.

US. Cl 260/268 DK Int. Cl C07d 51/72 Field of Search 260/268 BK Oct. 9,1973 [5 6] References Cited UNITED STATES PATENTS 3,171,837 3/1965 Freed260/268 DK Primary Examiner-Donald G. Daus Attorney-Samuel L. Welt etal.

[5 7 ABSTRACT 3 Claims, NoDrawings 3-(4-PHENYL-l 2, 6 D1 KETOPIPERAZINYL)-2-HYDROXY-PROPOXY)- ANILINE This a division of applicationSer. No. 882,297 filed Dec. 4, 1969 now US. Pat. No. 3,701,777.

BRIEF SUMMARY OF THE INVENTION The invention relates to aromatic ethersof the formula wherein R is amino, mono-(lower alkyl)amino, loweralkanoylamido, N-( lower alkyl) lower alkanoylamido, loweralkylsulfonylamido; R, is hydrogen or halogen; R, and R individually,are hydrogen, hydroxy, amino, halogen, lower alkyl or lower alkoxy; X isoxy or thio; and Y is methylene, hydroxymethylene, loweralkanoyloxymethylene, lower alkylsulfonyloxymethylene,arylsulfonyloxymethylene or carbonyl, and their pharmaceuticallyacceptable acid addition salts.

In another aspect, the invention relates to novel intermediates, forexample, the compounds of formulas wherein the various substituents areas hereinafter described, except that Z is halogen, loweralkylsulfonyloxy or arylsulfonyloxy, R" is lower alkanoylamido orN-(lower alkyl)lower alkanoylamido, R"' and R', are nitro, or R is nitroand R' is lower alkoxy, or R' is nitro and R is lower alkanoylamido andY is methylene or hydroxymethylene.

DETAILED DESCRIPTION OF THE INVENTION The invention relates to aromaticethers of the formula wherein R, is amino, mono-(lower alkyl)amino,lower alkanoylamido, N-(lower alkyl) lower alkanoylamido, loweralkylsulfonylamido; R is hydrogen or halogen; R and R individually arehydrogen, hydroxy, amino, halogen, lower alkyl or lower alkoxy; X is oxyor thio; and Y is methylene, hydroxymethylene, loweralkanoyloxymethylene, lower alkylsulfonyloxymethylene,arylsulfonyloxymethylene or carbonyl and their pharmaceuticallyacceptable acid addition salts.

As used herein, the term lower alkyl" denotes straight or branched chainlower alkyl of one to six carbon atoms, for example, methyl, ethyl orisopropyl, butyl, pentyl and the like. The term lower alkoxy" denoteslower alkyl ether groups in which the lower alkyl is as described above,for example, metliloxy, ethoxy, isopropoxy and the like. The termhalogen denotes chlorine, bromine, fluorine and iodine. Of the halogens,fluorine and chlorine are preferred.

The amino group, if desired, can be substituted by lower alkyl of one tosix carbon atoms, such as for example, methyl-ethyl-, propyl-, bu'tylorpentyl-amino and the like. The term lower alkanoyl denotes a residue ofone to six carbon atoms which is derived from a residue of a carboxylicacid of one to six carbon atoms, for example, formyl, acetyl, propionylor the like; acetyl is preferred. The lower alkylsulfonyl residues arederived from sulfuric acid substituted by lower alkyl, for example,methylsulfonyl, ethylsulfonyl and the like; methylsulfonyl is preferred.The term aryl" denotes phenyl or phenyl bearing a lower alkyl of one--four carbon atoms. Of these, p-tolyl is preferred.

Representative examples of the compounds of formula I of the inventionare:

rac.-O-

- 3-[4-(O-methoxy-phenyl)-l-piperazinyl1-2- hydroxy-propoxy} -aniline;

rac.-O-

{3-[4-(O-methoxy-phenyl)- l-piperalinyl 1-2- hydroxy-propoxy}-methylanilline;

rac.-O-

{3-[4-( O-amino-phenyl l -piperazinyl -2- hydroxy-propoxy} aniline;

rac.-2'-[3-(4-phenyll -piperazinyl)-2-hydroxypropoxy]-acetanilide;rac.-2'-[3-(4-phenyl-l-piperazinyl)-2-hydroxypropoxy]-propionanilide;

{3-[4-(p-chloro-phenyl)-1-piperazinyl]-2- hydroxy-propoxy} -acetanilide;rac.-2'-[3-(4-O-tolyl-l-piperazinyl)-2-hydr0xypropoxy]-acetanilide;

rac.2'-

{3-[4-(O-methoxy-phenyl)-1-piperazinyl]-2- hydroxypropoxy} -acetanilide;

a I3-[4-(2,4-dimethoxy-phenyl)-l-piperazinyll-Z- -thio] -acetanilide;rac.-4'-

H3-[4-(O-methoxy-phenyl)-l-piperazinyll-Z- hydroxy-propyl}-thio]-acetanilide;

{3-[4-(O-methoxy-phenyl)-l-piperazinyl1-2- hydroxy-propoxy} aniline; 2'-

{3-[4-(O-methoxy-phenyl)-l-piperazinyll-Z- hydroxy-propoxy}-acetanilide; and the like. Compounds of the invention can be preparedaccording to the following process variants:

a. A compound of the formula B2 II wherein R, is riitro, loweralkanoylarnido, N-(lower alkyl) lower alkanoylamido; R, is hydrogen orhalogen; X is oxy or thio; Y is methylene, hydroxymethylene, loweralkanoyloxymethylene, lower alkylsulfonyloxymethylene,arylsulfonyloxymethylene or carbonyl; Z is halogen, aryl or loweralkylsulfonyloxy or when taken together with Y and the end methylenegroup is is reacted with a compound of the formula III wherein R, andR';, individually are hydrogen, hydroxy, nitro, halogen, lower alkyl orlower alkoxy;

b. A compound of the formula R; IV

wherein R R and X are as previously described, is reacted with acompound of the formula wherein Y and Z are as previously described; andR" and R" individually, are hydrogen, nitro, halogen, lower alkyl orlower alkoxy;

c. A compound of the formula XCH YCH N wherein R',, R and X are aspreviously described and Y is methylene, hydroxymethylene or carbonyl,is reacted with a compound of the formula whFrEhfliQ and R", are aspreviously described; and Hal is halogen;

d. A compound of the formula R" VII VIII wherein R' R, and X are aspreviously described; Y- is methylene or carbonyl and A is halogen,lower alkylsulfonyloxy or arylsulfonyloxy, is reacted with a compound ofthe formula R". IX

wherein R, and R", are as previously described;

e. A compound of the formula w .7 r xcmW-0H=-Nm R; x

wherein R',, R,, X and Y are as previously described, is reacted with acompound of the formula wherein li'QTRH and A are as previouslydescribed;

f. A compound of the formula whereinR R R;,, R";, X and Y are aspreviously described, is reacted with a compound of the formula A- CPE-CH A i XIII wherein A is as previously described; or I g. The amidegroups in a compound of the formula wherein R,, R R R.,, X and Y'ar e tas previously described, are deoxygenated. The product obtained in agiven case above can be further modified. For example, a nitro group isreduced, an acylamido group is saponified, if desired, an amino group oramonoalkylamino group is acylated or an amino group is alkylated ifdesired, a carbonyl is reduced to the hydroxymethylene, if desired, ahydroxymethylene is esterified, if desired, and the compound of formulal obtained is optionally converted into a pharmaceutically acceptableacid addition salt.

Of the starting compounds of formula II, 2'-[2,3-epoxy-propoxy]-acetanilide is a known compound. On the other hand, thecorresponding 2-[2-hydroxy-3- halo(or tosyloxy)-propoxy]-acetanilide isa new compound which can, for example, be prepared by treating theepoxide mentioned hereinbefore in a protic solvent, for example, a loweralkanol such as methanol with an acid addition salt of a tertiary base,for example, pyridine hydrochloride or triethylamine hydrochloride and,

preferably at a temperature in the range of between about roomtemperature and the boiling point of the reaction mixture. The othercompounds of formula II can be prepared in an analogous manner.

The compounds of formula III, for example l-[O-methoxy-phenyl]-piperazine, are known compounds or can be prepared inaccordance with known procedures.

The reaction of the compounds of formula II with those of formula IIIwhen the compoundof formula II is the corresponding epoxide, isadvantageously carried out in a polar organic solvent, for example, alower alkanol such as methanol, or a cyclic ether such as dioxane at atemperature in the range of between about room temperature and theboiling temperature of the reaction mixture. The corresponding halo ortosyloxy compound of formula "is reacted in the presence of anacid-binding agent, for example, potassium or sodium carbonate, in alower alkanol such as ethanol or isopropanol, or in dimethylformamide ortetrahydrofuran, at a temperature in the range of between about roomtemperature and the boiling temperature of the reaction mixture.

The starting compounds of formula IV, for example, O-acetamido-phenol,are known compounds or can be prepared in accordance with knownprocedures.

On the other hand, the reaction components of formula V are knowncompounds. obtained the corresponding epoxide of formula V. Thecorresponding tosyloxy compound can be prepared by reaction of theepoxide obtained with p-toluenesulfonic acid.

The reaction of compounds of formula IV with the halo or tosyloxycompounds of formula V is advantageously carried out by converting thecompound of formula IV into the alkali salt with an alkali metalalkanolate and allowed to react with the compound of formula V at atemperature in the range of between about room temperature and theboiling temperature of the reaction mixture.

If the epoxide of a compound of formula V isutilized, the reaction witha compound of formula IV is preferably carried out in the presence of acatalytic amount of an organic or inorganic base, such as pyridine orpotassium hydroxide, in a polar solvent, preferably a lower alkanol suchas ethanol, or a cyclic ether such as dioxane, conveniently at atemperature in the range of between about room temperature and theboiling temper ature of the reaction mixture.

The compounds of formula VI are new compounds. 4'-[3-(1-piperazinyl)-2-hydroxy-propoxy]-acetanilide, for example, can beprepared by reacting 4-[2,3- epoxy-propoxy]-acetanilide withl-benzylpiperazine in an organic solvent, for example, an alkanol suchas ethanol, or a cyclic ether such as dioxane, at an elevatedtemperature, preferably at the boiling temperature of the reactionmixture and the benzyl residue is hydrogenolytically split off. Theother compounds of formula VI can be prepared in an. analogous manner.

The compounds of formula VII are known compounds or can be prepared inaccordance with known procedures.

The reaction of the compounds of formula VI with the compounds offormula VII is carried out utilizing a polar organic solvent, preferablyat a temperature in the range of about and 200C.

The compounds of formula VIII are new compounds. 4'- {3-[bis-(2-bromo[orbis-2-tosyloxy]-ethyl)-amino]- propoxy}-acet-anilide, for example, canbe prepared by reacting 4'-[3-bromo-propoxy]-acetanilide withdiethanolamine in the presence of an acid-binding agent, for example,potassium or sodium carbonate, and a polar solvent, preferably a loweralkanol such as ethanol or isopropanol, at an elevated temperature,conveniently at the boiling temperature of the reactionmixture. Theresulting di-ethanolamine compound can be halogenated utilizing ahalogenating agent, for example, phosphorus tribromide, phosphoruspentachloride or thionyl chloride, or tosylated by treatment withptoluenesulfonyl chloride in the presence of a base such as pyridine.The other compounds of formula VIII can be prepared in an analogousmanner.

The compounds of formula IX are known compounds or can be prepared inaccordance with known procedures.

The reaction of compounds;of formula VIII with compounds of formula IXis preferably carried out in the presence of an acid-binding agent,preferably sodium or potassium carbonate, arida polar solvent such asethanol, isopropanol or n-butanol, at an elevated temperature,conveniently at the boiling temperature of the reaction mixture. I

The compounds of formula X, except the nitro derivatives, are newcompounds. 2"-[3l-amino-2-hydroxypropoxy]-acetanilide, for example, canbe prepared by reacting a solution of ammonia in a lower alkanol, forexample ammonia in methanol, with 2'-[2,3-epoxypropoxy]-acetanilide at atemperature in the range of between about 0 and room temperature. Themixture of primary and secondary amine obtained is separated byfractional crystallization or by chromatography. The other compounds offormula X can be prepared in an analogous manner.

pmpbxfl-acet-anilide, for example, can be prepared by reacting2'-[2,3-epoxy-propoxy]-acetanilide with an excess of ethyleneimine at atemperature in the range of between about 0 and room temperature. The2-[3- aziridino-2-hydroxy-propoxy]-acetanilide obtained is reacted withO-anisidine in the presence of an acid, preferably maleic acid, at atemperature in the range of between about 0 and room temperature. Theother compounds of formula XII can be prepared in an analogous manner.

The compounds of formula XIII are known compounds or can be prepared inaccordance with known procedures.

The compounds of formula XII are preferably cyclized with al,2-dihalo[or ditosyloxy]-ethane of formula XIII at an elevatedtemperature, conveniently at the boiling temperature of the reaction,mixture.

The starting compounds of formula XIV are new compounds and can beprepared as hereinafter described.2-[3-(4-phenyl)-l-(2,6-diketopiperazinyl)-2-hydroxy-propoxy]-acetanilide, for example, can be prepared by reacting2'-[2,3-epoxy-propoxy]- acetanilide with 4-phenyl-2,6-diketo-piperazinein the presence of catalytic amounts of a base, for example, pyridineand a polar solvent, preferably a lower alkanol, such as ethanol, or acyclic ether such as dioxane, at an elevated temperature, convenientlyat boiling temperature of the reaction mixture. The other compounds offormula XIV can be prepared in an analogous manner.

The deoxygenation of the amide groups present in compounds of formulaXIV is conveniently carried out by reducing the compound of formula XIVwith a complex metal hydride, for example, with lithium aluminum hydridein an aprotic solvent, such as ethyl ether or tetrahydrofuran, at anelevated temperature, conveniently at the boiling temperature of thereaction mixture. Under the conditions mentioned, the carbonyl group Yis transformed into a hydroxymethylene group Y.

Compounds obtained which contain a nitro group are expediently reducedby chemical or catalytic means known to the art, for example, withtin/hydrochloric acid or hydrogen in the presence of a noble metalcatalyst. The hydrogenation is preferably carried out under normalpressure and room temperature, in an alkanol, preferably ethanol, weaklyacidified, for example, with hydrochloric acid, in the presence ofpalladium/charcoal as catalyst.

The compounds of formula I obtained in which R, is alkanoylamido can besaponified in a known manner with acidic or alkaline agents, forexample, with dilute aqueous alkali or aqueous acid. The saponificationis advantageously carried out with a percent aqueous hydrochloric acidat an elevated temperature, conveniently at the boiling temperature ofthe reaction mixture.

The compounds of formula I obtained in which R is amino can be acylatedin a known manner, for example, by treatment with an acid halide or acidanhydride. When employing alkanoyl or alkylsulfonyl halides and alkanoylanhydrides, the acylation is conveniently carried out in the presence ofa base, for example, pyridine or triethylamine, in the cold, preferablyat a temperature in the range of about 0 to about 5C. When employingalkanoyl anhydrides, the reaction may also be conducted in the presenceof a protic solvent, for example, a lower alkanol such as methanol orethanol, preferably at room temperature, and in the presence of diluteacetic acid.

The compounds of formula I obtained in which R is amino or acylamido canbe alkylated in a known manner, for example, with alkyl halides. Thereaction is conveniently effected at an elevated temperature, preferablyat the boiling point of the reaction mixture. The compounds of formulaI, in which R is amino, can be methylated with the aid offormaldehyde/formic acid. In so doing, the amine is dissolved in percentformic acid and treated with 40 percent formaldehyde. Upon the cessationof the evolution of carbon dioxide, the re action mixture is furtherheated on the steam bath before being worked up.

The compounds of formula I obtained in which Y is carbonyl can bereduced to compounds of formula I in which Y is hydroxy-methylene in aknown manner, for example, by treatment with a complex metal hydride,preferably a complex borohydride. The reduction is conveniently carriedout with the aid of an alkali metal borohydride, for example sodiumborohydride, in a lower alkanol such as ethanol or the like at atemperature in the range of between about room temperature and theboiling point of the reaction mixture.

The compounds of formula I in which Y is hydroxymethylene can beacylated in a known manner, for example, by reaction with a loweralkanoyl, lower alkylsulfonyl or arylsulfonyl halide or anhydride,preferably in the presence of a base, for example, pyridine ortriethylamine, at a temperature in the range of between about roomtemperature and the boiling point of the reaction mixture. An aminogroup that may be present will likewise be acylated under theseconditions.

The compounds of formula I wherein Y is hydroxymethylene are obtained asracemates. These, as well as the corresponding nitro-substitutedcompounds, can be separated into their optical antipodes in a knownmanner, for example, with the aid of optically active acids such astartaric acid.

The compounds of formula I form addition salts with inorganic or organicacids. Exemplary of these are: salts with hydrohalic acids such ashydrochloric or hydrobromic acid, salts with mineral acids, for example,with sulfuric acid, or also salts with organic acids, for example, withbenzoic acid, acetic acid, tartaric acid, citric acid, lactic acid orthe like.

The aromatic ethers of formula I prepared in accordance with theinvention are hypotensively active, and are therefore useful ashypotensive agents. Compounds of formula I wherein R is acylamido, R andR are hydrogen, R is hydrogen or lower alkoxy, X is oxy and Y ishydroxymethylene are preferred compounds.

9 {3- [4-(o-methoxy-phenyl)-l-piperazinyl]-2-hydroxypropoxy}-acetanilide has been found to exhibit a potenthypotensive activity. The toxicity of this compound is very low. In miceand rats, the lethal dose [LD on oral administration is about 300 mg/kg.The blood pressure-lowering action in mice has been demonstrated at adosage of 0.3 mg. p.o./kg.

Thus, the aromatic ethers of formula I can be used as hypotensivelyactive agents for controlling pathological high blood pressure,especially for controlling essential hypertonia. For such uses, up toabout 200 mg/day of the compounds of formula I, as exemplified by )-2-{3 -[4-(o-methoxy-phenyl)- l-piperazinyl1-2-hydroxypropoxy} -acetanilidecan be administered daily in. divided doses.

The compounds of formula I can be used in the form of pharmaceuticalpreparations which contain them or their salts in admixture with anorganic or inorganic pharmaceutically inert carrier suitable for enteralor parenteral application such as, for example, water, gelatin, gumarabic, lactose, starches, vegetable oils, polyalkyleneglycols, and thelike. The pharmaceutical preparations can be in solid form, for example,tablets, dragees, suppositories or capsules, or in liquid form, forexample, as solutions, suspensions or emulsions. The preparation may besterilized and/or contain additives, such as preservatives, stabilizers,wetting or emulsifying agents, or salts for varying the osmoticpressure. The pharmaceutical preparations can also contain additionaltherapeutically active substances.

EXAMPLE 1 Preparation of rac. 4-[3-(4-phenyl-l -piperazinyl)-2-hydroxy-propoxy]-acetanilide 2.07 g. of4'-(2,3-epoxypropoxy)-acetanilideand 1.7

g. of l-phenyl-piperazine are heated under reflux conditions in ml. ofethanol for 1 hour. The solvent is removed by evaporation under reducedpressure. The residual crystalline 4'-[3-(4-phenyl-l-piperazinyl)-2-hydroxy-propoxy]-acetanilide is dissolved in ethanol and madeCongo-acidic with ethanolic hydrochloric acid. The rac.4'-[3-(4-phenyl-l-piperazinyl)-2 hydroxy-propoxy]-acetanilidehydrochloride which precipitates after addition of absolute ether meltsat 25 3-254C. after recrystallization from ethanol/ether.

In an analogous manner, there is obtained:

By the reaction of2-(2,3-epoxypropoxy) acetanilide and lphenyl-piperaziner rac. 2-[3-(4-phenyl-1-piperazinyl)-2-hydroxy-propoxy]-acetanilide hydrochloride having ametling point of 208-209 C. (from methanol/ether);

By the reaction of 4'-(2,3-epoxypropoxy)-acetanilide andl-(p-chloro-phenyl)-piperazine: rac. 4-{3-[4-(p-chloro-phenyl)-l-piperazinyl1-2- hydroxy-propoxy} -acetanilidehaving a melting point of l93-l94C. (fromethanol');

By the reaction of 2'-(2,3-epoxypropoxy)-acetanilide andl-(p-chloro-phenyl)-piperazine: rac. 2'-{3-[4-(p-chloro-phenyl)-l-piperazinyl]-2- hydroxy-propoxy} -acetanilidedihydrochloride having a melting point of l94l95C. (from methanol/ethylacetate);

By the reaction of 2'-(2,3-epoxypropoxy)-acetanilide andl-(o-methoxy-phenyl)-piperazine: rac. 2'-{3-[4-(o-methoxy-phenyl)-l-piperazinyl]-2- hydroxy-propoxy} -acetanilidehydrochloride hav- 10 ing a melting point of l69-l70C. (frommethanol/ethyl acetate);

By the reaction of 2'-(2,3-epoxypropoxy)-acetanilide andl-(o-chloro-phenyl)-piperazine: rac. 2'- 3-[ 4-(o-chloro-phenyl l-piperazinyl -2- hydroxy-propoxy} -acetanilide hydrochloride having amelting point of 20l-202C. (from ethanol/- ether);

By the reaction of 2'-(2,3-epoxy-propoxy)- acetanilide andl-(p-tolyl)-piperazine: rac. 2-

2 {3- [4-p-tolyll -piperazinyl -2-1hydroxy-propoxy} -acetanilidehydrochloride having a melting point of 204-205C. (from ethanol/ether);

By the reaction of 2"(2,3-epoxypropoxy )-acetanilide and1-(m-methoxy-phenyl)-piperazine: rac. 2'- {3-[4-(m-methoxy-phenyl)- l-piperazinyl]-2- hydroxy-propoxy -acetanilide hydrochloride having amelting point of 97l00C. (from ethanol- /ethyl acetate);

By. the reaction of 2'-('2,3-epoxy-propoxy)- acetanilide andl-(o-tolyl)-piperazine: rac. 2'-[3- (4-o-tolyll -piperazinyl)-2-hydroxy-propoxy acetanilide hydrochloride having a melting point of216C. (from ethanol/ethyl acetate);

By the reaction of 5-chloro-2'-(2,3-epoxy-propoxy)- acetanilide andl-phenyl-piperazine: rac. 5- chloro-2'-[ 3-(4-phenyll-piperazinyl)-2-hydroxypropoxy1-acetanilide hydrochloride having amelting point of 20020lC. (from alcohol/ethyl acetate).

The 5 '-chloro-2'-( 2,3-epoxypropoxy)-acetanilide employed above can beprepared as follows:

37.1 g. of 4-chloro-2-acetaminophenol are introduced'to a solutioncontaining 9.6 g. of sodium hydroxide in 200 ml; of water. The solutionis treated all at once with 92.5 g. of epichlorohydrin and the mixtureis intensively stirred at room temperature for 20 hours. After washingwith water, the precipitate formed is recrystallized from ethylacetate/petroleum ether. The residual5-chloro-2'-(2,3-epoxypropoxy)-acetanilide melts at 8788C. afterrecrystallization from ethyl acetate/petroleum ether.

point of l57-l58C. (from methanol/ethyl acetate). The2'-(2,3-epoxypropoxy)-propionanilide employed above can be prepared inan analogous manner as described above for 5'-chloro-2-(2,3-epoxypropoxy) acetanilide. After recrystallization fromethyl acetate/petroleum ether, the 2'-(2,3-epoxypropoxy)- propionanilidemelts at 74-75C.

By the reaction of 2'-(2,3-epoxypropoxy)- propionanilide and l-(o-methoxyphenyl piperazine: rac. {3-[3-(o-methoxyphenyl)- 1-piperazinyl]-2- hydroxy-propoxy} -propionanilide hydrochloride having amelting point of l43-147C. (from methanol/ethyl acetate/ether);

By the reaction of 4'-( 2,3-epoxypropoxy propionanilide and l-(o-methoxyphenyl piperazine: rac. 4

{ 3-[4-(o-methoxy-phenyl)- l-piperazinyl1-2- hydroxy-propoxy}-propionanilide hydrochloride having a melting point of 190-l97C. (frommethanol/ethyl acetate/ether).

The 4'-(2,3-epoxypropoxy)-propionanilide employed above can be preparedin an analogous manner as described above for5'-chloro-2'-(2,3-epoxypropoxy)-acetanilide. After recrystallizationfrom ethyl acetate/petroleum ether, the 4'-(2,3-epoxy-propoxy)-propionanilide melts at l l7-120C.

By the reaction of 2'-( 2,3-epoxypropoxy)- propionanilide andl-(o-ethoxy-phenyl)- piperazine: rac. 2-

{3-[4-(o-ethoxy-phenyl)-l-piperazinyl1-2- hydroxy-propoxy}-propionanilide hydrochloride having a melting point of l76l78 C. (frommethanol/ethyl acetate/ether);

By the reaction of 2-(2,3-epoxypropoxy )-acetanilide and1-(o-ethoxy-phenyl)-piperazine: rac. 2-{3-[4-(o-ethoxy-phenyl)-1-piperazinyl]-2- hydroxy-propoxy} -acetanilidehydrochloride having a melting point of l57160C. (from methanol/ethylacetate/ether);

By the reaction of 3-(2,3-epoxypropoxy)-acetanilide andl-(o-methoxyphenyl)-piperazine: rac. 3= {3-[4-(o-methoxyphenyl lpiperazinyH-Z- hydroxy-propoxy} -acetanilide dihydrochloride having amelting point of 2OS207C. (from methanol/ethyl acetate);

By the reaction of 4-(2,3-epoxypropoxy)-acetanilide and1-(o-methoxyphenyl)-piperazine: rac. 4-{3-[4-(o-methoxyphenyl)-l-piperazinyl1-2- hydroxy-propoxy} -acetanilidehydrochloride having a melting point of 233C. (from methanol);

By the reaction of 2-(2,3-epoxypropoxy)-acetanilide andl-(o-hydroxyphenyl)-piperazine: hygroscopic rac. 2'- {3-[4-(o-hydroxyphenyl)-l-piperazinyl]-2- hydroxy-propoxy}-acetanilide hydrochloride(from ethyl acetate);

By the reaction of 2'-(2,3-epoxypropoxy)-acetanilide andI-(2,4-dimethoxyphenyl)-piperazine: rac. 2'-{3-[4-(2,4-dimethoxyphenyl)- l-piperazinyl1-2- hydroxy-propoxy}-acetanilide dihydrochloride having a melting point of 223225C. (frommethanol);

By the reaction of 3 '-(2,3-epoxypropoxy)- propionanilide andl-(o-methoxyphenyl piperazine: rac. 3"-

{3-[4-(o-methoxyphenyl)- l -piperazinyl1-2- n hydroxy-propoxy}-propionanilide dihydrochloride having a melting point of 205-206C.(from ethanol).

The 3-(2,3-epoxypropoxy)-propionanilide employed above can be preparedin an analogous manner as described above. After recrystallization fromethyl acetate/petroleum ether, the 3'-(2,3-epoxypropoxy)- propionanilidemelts at 67-69C.

By the reaction of 4-(2,3-epoxypropoxy)- butyranilide andl-(o-methoxyphenyl)-piperazine:

rac. 4 {'3-[ 4-( o-methoxyphenyl 1 -piperazinyl -2- hydroxypropoxy}-butyranilide dihydrochloride having a melting point of 215C. (fromethanol); By the reaction of 4-(2,3-epoxypropoxy)- butyranilide and1-(p-methoxyphenyl)-piperazine: rac. 4'- 3-[ 4-(p-methoxyphenyl l-piperazinyl]-2- hydroxypropoxy} -butyranilide having a melting point of153154C. (from ethanol). The 4-(2,3-epoxypropoxy)-butyranilide employedabove can be prepared in an analogous manner as described above. Afterrecrystallization from ethyl acetate/petroleum ether, the4-(2,3-epoxypropoxy)- butyranilide melts at l02-103C.

EXAMPLE 2 Preparation of 4'- 3 [4-(o-methoxy-phenyl)- 1-piperazinyl]-propoxy} -acetanilide g 5.4 g. of4'-(3-bromopropoxy)-acetanilide, 4 g. of l-(o-methoxy-phenyl)-piperazine, 1.4 g. of potassium carbonate and a fewcrystals of potassium iodide are heated under reflux conditions in 30ml. of ethanol for 24 hours. The reaction solution is filtered hot andthereafter evaporated under reduced pressure. The residual 4'-{3-[4-(o-methoxy-phenyl)-l-piperazinyl1-propoxy} -acetanilide is madecongo-acidic with ethanolic hydrochloric acid to form the hydrochloridewhich melts at 25926lC. (dec.) after recrystallization frommethanol/ethyl acetate.

In an analogous manner there is obtained:

By the reaction of 2-(3-bromopropoxy)-acetanilide andl-(o-methoxyphenyl)-piperazine: 2 3-[4-(o-methoxyphenyl)-l-piperazinyl1-propoxy} -acetanilide dihydrochloride having a melting point of l18120C.

EXAMPLE 3 Preparation of rac.-2'-{3-[4-(o-methoxyphenyl)-1-piperazinyl]-2-hydroxypropoxy}-N-methylacetanilide 11 g. of 2-(2,3-epoxypropoxy)-N-methyl-acetanilideand 9.6 g. of 1-(o-methoxyphenyl)-piperazine are heated under refluxconditions in ml. of ethanol for 1 hour. The solvent is removed byevaporation under reduced pressure. The residual oily rac.-2'-3-[4-(o-methoxyphenyl)-1-piperazinyl]-'2hydroxypropoxy}-N-methylacetanilideis dissolved in ethyl acetate, converted into the hydrochloride byaddition of alcoholic hydrochloric acid up to the congo-acidic reactionand precipitated with ether. For purification, the product is once moretransformed into the base and again converted into the hydrochloride inthe same manner. After recrystallization from ethanol/ethyl acetate,rac.-2- {3-[4-(o-methoxyphenyl)-1-piperazinyl]-2-hydroxy propoxy}-N-methylacetanilide dihydrochloride melts at about C.

The oily 2'-(2,3-epoxy-propoxy)-N- methylacetanilide employed above canbe prepared in an analogous manner as described in Example l, n,,.=1.523.

EXAMPLE 4 Preparation of rac.-4- {3-[4-(o-methoxyphenyl)- l-piperazinyl]-2-hydroxypropoxy} -acetanilide l .3 g. of 4-(3-chloro-2-hydroxy-propoxy)- acetanilide and 0.9 g. ofl-(o-methoxyphenyl)- piperazine are treated with 0.5 g. of sodiumbicarbonate and a few crystals of sodium iodide and introduced into amixture of ml. of dimethylformamide and 20 ml. of tetrahydrofuran. Thereaction mixture is heated under reflux conditions for 24 hours. Aftercooling, it is poured into water and extracted with ethyl acetate. Therac.-4'- {3 4-( o-methoxy-phenyl l -piperazinyl]-2-hydroxy propoxy}-acetanilide remains after evaporation of the solvent is dissolved inethyl acetate and converted to the hydrochloride by addition ofalcoholic hydrochloric acid up to the congo-acidic reaction. Thehydrochloride salt melts at 23223 3C. after recrystallization frommethanol.

The 4 3-chloro-2-hydroxy-propoxy)-acetanilide employed above can beprepared in the following manner:

4.1 g. of 4'-(2,3-epoxypropoxy)-acetanilide and 4.6 g. of pyridinehydrochloride are heated under reflux conditions in 20 ml. of methanolfor 1 hour. The residue which remains after evaporation of the solventis dissolved in n-butanol, and the solution is repeatedly extracted withwater. The organic phase is separated and evaporated. The residual oily4-(3-chloro-2- hydroxy-propoxy)-acetanilide is dissolved in ethylacetate/cyclohexane and crystallized. After recrystallization from ethylacetate/cyclohexane, 4'-(3-chloro-2- hydroxy-propoxy)-acetanilide meltsat l06-108C.

EXAMPLE 5 Preparation of 4'- with alcoholic hydrochloric acid to acongo-acidic reaction. The crystalline 4'- 3-[ 4-(o-methoxyphenyl)- l-piperazinyl]-propyl}-thi fl -acetanilide hydrochloride precipitates andmelts at 234-236C. after recrystallization from methanol.

The 4-(3-bromo-propylthio)-acetanilide employed above can be prepared asfollows:

16.7 g. of 4-acetaminothiophenol, 60 ml. of ethanol, 8 g. of 50 percentaqueous caustic soda and 156 g. of 1,3-dibromopropane are heated underreflux conditions for 3 hours. The excess 1,3-dibromopropane is removedby steam-distillation. The oil which separates out is taken up inchloroform. Thereafter, the organic phase is washed twice with 1Ncaustic soda and with water to a neutral reaction. The oily 4-(3-bromopropylthio)-acetanilide which remains after evaporation of thesolvent is chromatographed on a column of neutral aluminum oxide[activity grade 1] [eluting agent: benzene]. After recrystallizationfrom dilute ethanol, 4-(3-bromo-propylthio)-acetanilide melts at C.

EXAMPLE 6 Preparation of rac. 4' 3-[ 4-( o-methoxyphenyl l -piper.azinyll-2-hydroxypropyl}-thio] -acetanilide 2.2 g. of 4'-(2,3-epoxypropylthio)-acetanilide and 1.9 g. of l-(o-methoxyphenyl)-piperazine are heatedunder reflux conditions in 20 ml. of ethanol for 1 hour. The oily rac.4' 3-[4-(o-methoxyphenyl)- l-piperazinyl1-2-hydroxypropyll-thio]-acetanilide which remains after evaporation of the solvent is dissolvedin ethyl acetate and converted into the hydrochloride by addition ofalcoholic hydrochloric acid. After recrystallization from methanol/ethylacetate, 7 7 rac. W H 4f 3- [4-( o-methoxyphenyl l -piperazinyl-2-hydroxypropyl}-thio] -acetanilide hydrochloride melts at 21 l-- 212C.

The 4'-(2,3-epoxypropylthio)-acetanilide employed above can be preparedas follows:

33.4 g. of p-acetaminothiophenol are introduced to a solution of 8.8 g.of sodium hydroxide in water. The solution is treated with 27.6 g. ofepichlorohydrin with stirring. The reaction proceeds exothermically andis controlled by cooling. Thereafter, the reaction mixture is stirred atroom temperature for 12 hours. The beigecolored4-(2,3-epoxypropylthio)-acetanilide which precipitates is washed withwater. After recrystallization from ethyl acetate/cyclohexane, the4'-(2,3- epoxypropylthio)-acetanilide melts at 82C.

EXAMPLE 7 Preparation of rac.-4- {3-[4-(o'methoxyphenyl l-piperazinyl]-2-hydroxypropoxy} -acetanilide V 0.75 g. ofp-acetaminophenol are introduced to a so lution of mg. of sodium in 30ml. of absolute methanol. The mixture is treated with ll.4 g. ofl-chloro-2 hydroxy-3-[ 4-( o-methoxyphenyl l. -piperazinyl propane andheated under reflux conditions for 20 hours. Sodium chloride whichprecipitates is removed by filtration. The filtrate is evaporated todryness. The re sidual rac.-4- 3-[4-(o-methoxyphenyl)- l-piperazinyl]-2-hydroxypropoxy}-acetanilide is converted into thehydrochloride by addition of alcoholic hydrochloric acid up tocongo-acidic reaction. The rac.-4'- 3-[4-(o-methoxyphenyl l-piperazinyl1-2-hydroxypropoxy}-acetanilide hydrochloride melts at228-230- C. after recrystallization from methanol.

The 1-chloro-2=hydroxy-3-[4-(o-methoxyphenyl)-lpiperazinyl]-propaneemployed above can be prepared as follows:

3.8 g. of l-(o-methoxyphenyl)-piperazine are dissolved in 20 ml. ofmethanol and treated with 2 g. of epichlorohydrin. The crystallinel-chloro-2-hydroxy-3- [4-(o-methoxyphenyl)- l-piperazinyl1-propane whichseparates after 72 hours at room temperature, melts at l07-107.5C. afterrecrystallization from methanol.

EXAMPLE 8 Preparation of rac.-4'- 3-[4-(o-aminophenyl)- l -piperazinyl-2-hydroxypropoxy} -acetanilide hydrochloride 0.73 g. of rac.-4-[3-(1-piperazinyl)-2-hydroxypropoxy}-acetanilide hydrochloride, 0.34 g. ofpotassium hydroxide and 0.32 g. of o-chloronitrobenzene in ml. ofn-butanol are reacted under reflux conditions for 12 hours. Theresulting reaction mixture is evaporated under reduced pressure, and theresidue is taken up in chloroform. The solution is washed with water andevaporated to dryness. The residual rac.-4-{3-[4-(o-nitrophenyl)-1-piperazinyl]-2-hydroxypropoxy} -acetanilide ispurified by adsorption on silica gel {elution mixture: methanol]. Thehydrochloride salt melts at 243C.

0.45 g. of the foregoing compound is dissolved in 200 ml. of ethanol (95percent) with mild heating and hydrogenated in the presence of 50 mg. ofplatinum oxide at room temperature. The hydrogenation is carried outuntil the theoretical uptake of hydrogen is completed. The catalyst isremoved by filtration. The filtrate is brought to a congo-acidicreaction with ethanolic hydrochloric acid and evaporated to drynessunder reduced pressure. The residual rac.-4'- {3-[4-( o-aminophenyl l-piperazinyl]-2-hydroxypropoxy} -acetanilide hydrochloride, afterrecrystalliz'ation from ethanol/ethyl acetate, has a melting point of232234C.

EXAMPLE 9 Preparation of {3-[4-( o-methoxyphenyl 1-piperazinyl]-propoxy} -aniline dihydrochloride 1.0 g. ofo-{n3-[bis-(2-chloroethyl)-amino[-propoxy}' -nitrobenzene and 0.3 g. .ofo-anisidine in 20 'ml. of n-butanol are heated under reflux conditionsfor 8 hours. The reaction mixture is then treated with 150 mg. ofpotassium carbonate. Thereafter, the reaction mixture is heated underreflux conditions for another 24 hours and subsequently extracted withwater. The aqueous extract is washed with ethyl acetate, made alkalineand extracted with chloroform. The chloroform extract is evaporated todryness. The residual o- {3 -[4-(o-methoxy-pheny1)-l-piperazinyl]-propoxy} -nitrobenzene is .converted to the hydrochloride".alt

by known procedures. After recrystallization from methanol/ether, thehydrochloride has a melting point of l95-196C.

0.8 g. of the foregoing compound are dissolved in 100 ml. of ethanol (95percent) and hydrogenated in the presence of 50 mg. of platinum oxide atroom temperature. The hydrogenation is continued until the theoreticaluptake of hydrogen is completed. The catalyst is removed by filtration.The filtrate is made congoacidic with ethanolic hydrochloric acid andevaporated to dryness under reduced pressure. The residual o-{3-[4-(o-methoxyphenyl)-1-piperazinyl]-propoxy} -anilinedihydrochloride, after recrystallization from methanol/ethyl acetatemelts at 250C. 0

The o- {3-[bis-(2-chloroethyl)-amino]-propoxy} -nitrobenzene employedabove can be prepared as follows:

28 g. of o-(3-bromopropoxy)-nitrobenzene, 10.1 g. of diethanolamine, 25g. of potassium carbonate, a crystal of potassium iodide, 250 ml. ofisopropanol and 30 ml. of water are heated under reflux conditions for24 hours. The reaction mixture is evaporated under reduced pressure. Theresidue is dissolved in 50 ml. of chloroform and 50 ml. of water. Thechloroform phase is separated, dried over potassium carbonate andevaporated. The residual o- 3-[bis-(2-hydroxyethyl)-amino]-propoxy}nitrobenzene is converted to the hydrochloride salt by the addition ofalcoholic hydrochloric acid. The hydrochloride, after recrystallizationfrom ethanol/ethyl acetate, melts at -91C.

1.6 g. of the foregoing compound is suspended in 20 ml. of methylenechloride and treated with 1.4 g. of thionyl chloride. The reactionmixture is heated for 30 minutes under reflux conditions. The resultingclear solution is evaporated to dryness under reduced pressure. Theresidual o-{3-[bis-( 2-ch1oroethyl)-amino]-propoxy} -nitrobenzene, afterrecrystallization from methanol/ether, melts at 133-135C.

EXAMPLE 10 Preparation of rac.-4'-

propoxy} -butyranilide 1.7 g. of rac.-4'-(3-amino-2-hydroxy-propoxy)-butyranilide, 1.25 g. of bis-N,N-(2-bromoethyl)-oanisidine, 0.56 g. ofpotassium hydroxide in 50 ml. of n-butanol and 3 drops of water areheated over a 20- hour period under reflux conditions. Then, thereaction mixture is evaporated under reduced pressure. The residue isdissolved in chloroform. The chloroform extract is washed with water andevaporated. The residual rac. 4'-

{3-[4-(p-methoxyphenyl)-1-piperazinyl]-2-hydroxy- A propoxy}-butyr-anilide is purified by adsorption on silica gel [elution solvent:methanol] and has a boiling point of 152C.

The rac. 4-(3-amino-2-hydroxy-propoxy)- butyranilide employed above canbe prepared as follows:

12.0 g. of 4-(2,3-epoxypropoxy)-butyranilide are treated with stirringover a l-hour period with 250 ml. of a solution containing ammonia andmethanol (about 10 percent). The reaction mixture is allowed to stand atroom temperature for 24 hours and after the addition of 10 ml. of moreof an aqueous ammonia solution, is allowed to stand in the cold for 12hours. Subsequently, the reaction mixture is filtered, and the filtrateis evaporated under reduced pressure. The residual rac. 4'-(3-amino-2-hydroxy-propoxy)-butyranilide, after recrystallization fromethyl acetate, has a melting point of 138l40C.

EXAMPLE 1 1 Preparation of rac. 4 {3-[4-(o-methoxyphenyl)-1-piperazinyl]-2-hydroxypropoxy} -butyranilide 17 propoxy -butyranilide ispurified by adsorption on silica gel [elution solvent: ethyl acetate].The resulting base can be converted to the dihydrochloride in the usualmanner and has a melting point of 215C. (from ethanol).

The rac. 4'- {3-[2-(o-anisidino-ethyl)-amino]-2-hydroxy-propoxy} Vbutyranilide employed above can be prepared as follows:

12.0 g. of 4'-(2,3-epoxy-propoxy)-butyranilide are treated with 50 ml.of methanol, 50 ml. of ethylenediamine and a trace of potassiumhydroxide. The reac tion mixture is allowed to stand at room temperaturefor 12 hours. The excess ethylenediamine and the solvent are evaporatedunder reduced pressure. The residual rac. 4-[3-(l-aziridinyl)-2-hydroxy-propoxy]- butyranilide, after tworecrystallizations from ethyl acetate, has a melting point of 1081l0C.

5.6 g. of rac. 4'-[3-( l-aziridinyl)-2-hydroxypropoxy]-butyranilide and2.5 g. of o-anisidine are dissolved in 25 ml. of methanol and treatedwith a solution containing 5.6 ml. of maleic acid in ml. of methanol.The reaction mixture is allowed to stand at room temperature for 72hours. Thereafter, the reaction mixture is evaporated under reducedpressure. The base is liberated by the addition of an excess of 1Nsodium hydroxide solution and is extracted with chloroform. Thechloroform extract is evaporated. The residual rac. 4-{3-[2-(o-anisidino-ethyl)-amino]-2-hydroxy-propoxy} -butyranilide ispurified by adsorption on silica gel [elution solvent: methanol]. Afterrecrystallization from ethyl acetate, the product melts at l03-104C.

EXAMPLE 12 {3-[4-(o-methoxyphenyl)- l -piperazinyl]-2-hydroxy-propoxy}-methyl-aniline having a melting point of 198C. (frommethanol).

EXAMPLE 13 Preparation of rac. {3-[ 4-(o-methoxyphenyl l-piperazinyl]-2-hydroxypropoxy} -methanesulfonanilide 3-[4-(o-methoxyphenyl l -piperazinyl Z-hydroxypropoxy}-methanesulfonanilide is converted to the crystalline hydrochloride bythe addition of ethanolic hydrochloric acid and ethyl acetate. Afterrecrystallization from alcohol/ethyl acetate/ether, the product has amelting point of 2l7-2l8C.

In an analogous manner there is obtained:

the

By reaction of o- {3-[4-( o-methoxyphenyl l -pipe1'azinyl] propoxyl}-aniline: 2- {3-[4-(o-methoxyphenyl 1 -piperazinyl]- A propoxy}-methanesulfonanilide dihydrochloride having a melting point of200-201C. (from ethanol/ethyl acetate).

EXAMPLE 14 Preparation of rac. 2'- 3-[4(o-acetamido-phenyl)-l-piperazinyl]-2- hydroxy-propoxy} -acetanilide 2.4of rac. o-

{2-[4-(o-aminophenyl)-l-piperazinyl]-2-hydroxy propoxy} -aniline aredissolved in 20 ml. of acetic acid and treated with l g. of aceticanhydride. The reaction mixture is allowed to stand at room temperaturefor 12 hours. The solvent is removed under reduced pressure. The residueis dissolved in ethyl acetate, and the resulting solution is treatedwith ethanolic hydrochloric acid. The precipitated rac. 2'-{3-[4-(o-acetamido-phenyl)- l-piperazinyl1-2- hydroxy-propoxy}-acetanilide, after recrystallization from ethyl acetate, has a meltingpoint of 78-80C.

The rac. {3-[4-(o-aminophenyl)-l-piperazinyl1-2- hydroxypropoxy}-aniline employed above can be prepared as follows:

2 g. of 2-(2,3 -epoxy-propoxy)-nitrobenzene and 2.1 g. ofl-(o-nitrophenyl)-piperazine in 20 ml. of ethanol percent) are heatedunder reflux conditions for 1.5 hours. The solvent is evaporated underreduced pressure. The residue is dissolved in ethyl acetate andacidified to a Congo-acidic reaction with alcoholic hydrochloric acid.The rac. o- 3-[4-(o-nitro-phenyl)-1-piperazinyl]-2-hydroxypropoxy}-nitrobenzene hydrochloride, after recrystallization fromethanol/isopropanol, has a melting point of 203-205C.

1 g of rac. o-

propoxy}-nitrobenzene is dissolved in 50 ml. of ethanol (95 percent) andhydrogenated with 50 mg. of platinum oxide at room temperature undernormal pressure. The hydrogenation is stopped upon the theoreticaluptake of hydrogen. The catalyst is removed by filtration. The filtrateis weakly acidified with alcoholic hydrochloric acid and evaporated todryness under reduced pressure. The residual rac. o-

{-3 4-( o-aminophenyl 1 -piperazinyl -2-hydroxypropoxy} -anilinetrihydrochloride, after recrystallization from ethanol/ethyl acetate,has a melting point over 300C.

In an analogous manner there is obtained:

By the reaction of rac. o-

{3-[4-(o-methoxyphenyl)-l-piperazinyl1- Zhydroxy-propoxy} -aniline: rac.2

{3-[4-(o-methoxyphenyl)- l -piperazinyl]-2 hydroxy-propoxy -acetanilidehydrochloride having a melting point of l80182C. (from ethanol- /ethylacetate); A

By the reaction of {3-[4-(o-methoxy-phenyl)- l -piperazinyl]- propoxy}-aniline: 2-

3-[4-(o-methoxyphenyl l -piperazinyl]- propoxy} -acetanilidedihydrochloride having a melting point of 2l8-222C. (from ethanol/ethylacetate).

EXAMPLE Preparation of rac. 2'- l3-[ 4-( o-methoxyphenyl)- l-piperazinyl]-2-acetoxypropoxy }-acetanilide 4.35 g. of rac. 2'-

'propoxy -acetanilide in the form of the hydrochloride, has a meltingpoint of l-202C.

In an analogous manner there is obtained:

By the reaction of rac. 4'-

3-[4-(o-methoxyphenyl)-l-piperazinyl]-2- l hydroxy-propoxy}-acetanilide: rac. 4'-

{3-[4-(o-methoxyphenyl)-l-piperazinyl]-2 acetoxy-propoxy} -acetanilidehydrochloride having a boiling point of 175C.

EXAMPLE 16 Preparation of rac. 2-

, 3-[4-(o-methoxyphenyl)- l -piperazinyl]-2-acetoxypropoxy}-acetanilide0.5 g. of rac.{3-[4-(o-methoxyphenyl)-l-piperazinyl]-2-hydroxypropoxy}-aniline isdissolved in 5 ml. of glacial acetic acid, treated with 0.5 g. of aceticanhydride and allowed to stand at room temperature for 24 hours. Thereaction mixture thereafter is poured in water and made slightlyalkaline through the addition of 1N sodium hydroxide solution (pH about9). The base is exhaustively extracted with chlorofrom. The chloroformextract is washed with water and evaporated under reduced pressure. Theresidual rac. 2'- l3-[4-(o-methoxyphenyl)- 1-piperazinyl]-2-acetoxypropoxy}-acetanilide is converted to thehydrochloride by known procedures and has a melting point of 20 l- 202C.(from methanol/ether).

EXAMPLE 17 Preparation propoxyl-nitrobenzene and 36.0 g. of 0,0-dibenzoyltartaric acid are dissolved in 3,500 ml. of hot methanol. Thesolution is allowed slowly to cool to room temperature. The o-3-[4-(o-methoxyphenyl)- l -piperazinyl]-2-hydroxypropoxy} -nitrobenzenedibenzoyl tartrate separates out in the crystalline form. The salt ofthe antipode remains in solution and can be recovered out of this. Thesalt of the antipode, after recrystallization from 3,200 ml. ofmethanol, melts at 169C.; [a] ,,=+36.6- C. (in dimethylsulfoxide, C 1).

The resulting salt of the antipode is added to 200 ml. of 1N sodiumhydroxide solution and 500 ml. of chloroform. The mixture is agitated.The formed free base, after recrystallization from ethylacetate/petroleum ether, has a melting point of -77C.; [a] 144C. [inethanol, C=l].

3.0 g. of o- 3-[4-(o-methoxyphenyl)- l-piperazinyl]-2-hydroxypropoxy}-nitrobenzene are dissolved in ml. of ethanol andhydrogenated in the presence of platinum oxide. The hydrogenation iscontinued until the theoreti cal uptake of hydrogen is completed. Thecatalyst is removed by filtration. The solvent is evaporated underreduced pressure. The residual o- 3-[4-(o-methoxyphenyl)- l-piperazinyl]-2-hydroxypropoxy}-aniline [the trihydrochloride of which melts at 263;[a]'- =+3 l.8C. (in water, C=l )]is dissolved in 20 ml. of 3N aceticacid and treated with l g. of acetic anhydride. The reaction mixture isallowed to stand at room temperature for 12 hours and thereafter isevaporated under reduced pressure. The residue is dissolved in ethylacetate and treated with ethanolic hydrochloric acid. The precipitated2' 3-[4-(o-methoxyphenyl)-l -piperazinyl]-2-hydroxypropoxy}-acetanilide,after recrystallization from ethyl acetate, has a melting point of179C.; [a] =+4l 1- C. (in water, C=1).

The antipode can be obtained in a similar manner by the treatment ofrac. o-3-[4-(o-methoxyphenyl)-l-piperazinyl]-2-hydroxypropoxy}-nitrobenzenewith 0,0-dibenzoyltartaric acid.

EXAMPLE 18 Tablets are prepared of the following composition:

acetanilide hydrochloride 10 mg. Lactose 63 mg. Corn Starch 74 mg.Talcum 2.7 mg. Magnesium stearate 0.3 mg. Total 150.0 mg.

The 2'- 3-[4-(o-methoxy-phenyl)- l-piperazinyl]-2-hydroxypropoxy}-acetanilide hydrochloride is mixed withthe lactose and the corn starch and granulated with the aid of ethanol.The granulate is dried, mixed with talcum and pressed to tablets.

Individual weight of one tablet mg.

Active substance weight of one tablet 10 mg.

We claim:

1. A compound of the formula wherein i is aminofmonodower alkyl)amino,lower alkanoylamido of one to six carbon atoms, or primary or secondarylower alkylsulfonylamido of two to six carbon atoms; R is hydrogen orhalogen; R and R individually, are hydrogen, hydroxy, halogen, primaryor secondary lower alkyl of one to six carbon atoms or primary orsecondary lower alkoxyl of one to six carbon @2 3 UNITED STATES PATENTOFF-ICE CERTIFICATE OF CORRECTION Patent No. ,602 Date-d October 9, 1973Inventoflg) Albrecht Edenhofer and Hans Spiegelberg It is certified thatextra: appears in the-'aboveddentified' patent and that said LettersPatent are hereby corrected as shown below:

Coverrpage, "L541 3- (4-PHENYL*1 2,6 DI KETO PIPERAZINYL) 2-HYDROXY-PROPOXY) -ANILIN E" Should be:

C'over page, after [ZIJAppL No.: 269,680" insert:

Foreign Application Priority Data December 24, 1968 Switzerland1926,9/68

Column 22, claim 1, line 1, "atoms is oxy" should be:

atoms; X is oxy Signed and sealed this 6th day of August 1974.

( EAL) Attest: I v

MCCOY M. GIBSON, JR. 0. MARSHALL'DANN Attesting Officer Commissioner ofPatents

2. The compound in accordance with claim 1, wherein R1 is o-amino; R2and R3 are hydrogen; R4 is o-methoxy; X is oxy and Y'' ishydroxymethylene, i.e.,o-3-(4-(o-methoxy-phenyl)-1-(2,6-diketo-piperazinyl))-2-hydroxy-propoxy-aniline.
 3. The compound in accordance with claim 1, wherein R1 iso-amino; R2, R3 and R4 are hydrogen; X is oxy and Y'' ishydroxy-methylene, i.e., o-(3-(4-phenyl)-1-(2,6-diketo-2-hydroxy-propoxy)-aniline.